What is a vaccine and how does it prevent/reduce disease for an individual and for a population?
When a person is infected by a pathogen for the first time, their immune system gradually learns to recognise it, and then potently and specifically neutralise it. But this process takes one to two weeks, in which time, the person suffers from the disease and produces many copies of the pathogen, potentially infecting other people. A vaccine is a non-infectious, inactivated version of a pathogen, or part of a pathogen that can be injected into a person’s body to train their immune system to recognise the wild, harmful pathogen and rapidly neutralise it. This ability to quickly recognise and neutralise future infections or immune memory prevents severe disease in the individual and also reduces the chances of spreading the disease to others.
As more and more people in a population have an immune memory to quickly fight off a particular infection, the chances of it spreading get lower and lower. A population reaches herd immunity for a disease when each infected person spreads the disease to less than one other person, on average. The chances of disease spread depend on biological factors such as the pathogen’s virulence but also societal factors, such as physical distancing measures. Vaccinating as many people in a population as possible is one important way to reduce infection spread. But it is just as important to maintain physical distancing and other measures to reduce spread, especially to end the COVID19 pandemic.
What are the different phases of vaccine approval under normal (non-pandemic) situations? What are the parameters to gauge success at each stage?
A vaccine is a preparation that contains one or more pathogens in inactivated (also known as avirulent) form. Alternatively, the preparation may contain only some part of the disease-causing organism or it may comprise an artificial substance that mimics a pathogen. The main purpose of any given vaccine is to generate immune response in the recipient that is sufficient enough to provide protection against a particular disease. This leads to priming of the recipient’s immune system against the foreign pathogen. If this particular pathogen is encountered by the recipient in the future, the recipient’s immune system will be able to act more swiftly and effectively against the pathogen and hence protection is ensured in the recipient.
In general, accessibility to a new vaccine spans a period of 10 – 15 years, beginning from the discovery of a new vaccine candidate to the licensure of the vaccine formulation. The overall process of vaccine development is rigorous, involving careful study design and continuous monitoring throughout to efficiently determine the final vaccine formulation and analyse whether the vaccine is safe, tolerable and does not outweigh the benefits of protection. The various phases involved in the research and development of a vaccine are mentioned below:
1. Exploratory phase and pre-clinical studies
- To identify a novel vaccine candidate
- To evaluate safety and potential to prevent the ‘disease in question’
Tested in: Animals like mouse, hamster, rabbit, rat, monkeys, etc. that mimic the targeted human disease. The testing involves ‘challenge experiments’ to analyse the level of protection by the vaccine candidate against a virus (or another pathogen).
Outcome: A suitable vaccine candidate is identified which is then taken forward to Phase I clinical trials in humans. The pre-clinical phase allows decision-making for further development of vaccines. If the immune response elicited is insufficient, the vaccine candidate is abandoned.
Approval methodology: The vaccine candidate must not be toxic, should generate binding and neutralizing antibodies against the target pathogen. The tests include toxicity analysis, immunoassays like ELISA, virus neutralization assays etc.
2. Phase I clinical trials
- To evaluate whether the vaccine is safe for use in humans
- To confirm if it generates an immune response in the recipients
- To estimate the appropriate dosage and route of administration of the vaccine
Tested in: Small numbers of healthy adult volunteers, who are preferably enrolled and observed at a tertiary care hospital. The reason for such preference is to ensure immediate health care service, just in case any adverse reaction post-vaccination occurs.
Outcome: Vaccine safety, tolerability and dosage is identified.
Approval methodology: Antibodies and other parameters of immunity generated as a result of the vaccine are assessed. The vaccine must not be toxic. It must be able to generate antibodies that bind and neutralize the pathogen, thereby exhibiting effective protection against the pathogen. Apart from this, T‑cell immune responses are also assessed by highly sensitive and robust immunological techniques.
3. Phase II clinical trials
- To further assess the immune responses generated by the vaccine. This includes evaluation of types and magnitude of immune responses
- To determine the exact dose and immunization schedule
Tested in: Larger numbers (compared to Phase I) of volunteers having characteristics (like age, health conditions, etc.) similar to the target population (people more likely to be affected by the disease in question; for instance, COVID19 at present). In this phase, vaccines are administered in some of the volunteers. The non-recipients form the control (or placebo) group, who receive a shot of saline instead of the vaccine formulation.
Outcome: Comparative analysis of vaccine effects on recipients and non-recipients. Efficacy end-points and immunogenicity are determined.
Approval: Generation of sufficient levels of neutralizing antibodies against the target pathogen. Achievement of expected seroconversion rates (time period for antibody development).
4. Phase III clinical trials
Aims: To assess the efficacy and safety of the vaccine so as to progress towards registration and marketing of the vaccine.
Tested in: Thousands of individuals representing the targeted population are enrolled. Similar to phase II, vaccine is administered to some, while others form the control group.
Outcome: This phase generates more conclusive data regarding the effects of the vaccine in the targeted population. In other words, the vaccine efficacy and final formulation is determined based on the results of phase III trial.
Approval: The success of phase III trial is dependent on the vaccine efficacy. Vaccine efficacy is defined as the percent reduction in incidence (of an infection) among vaccinated individuals. It is calculated by the following formula:
(IU-IV/IU)*100 = (1‑IV/IU)*100 % =(1‑RR)*100%
Where, IU = Incidence in placebo population (number who get disease amongst placebo / total number of placebo or control)
IV = Incidence in vaccinated population (number who get disease amongst vaccinated / total number given vaccine )
RR = Relative Risk
The results of all the clinical trials are carefully reviewed to evaluate the efficacy and safety of the vaccine. This follows application for regulatory and public health policy approvals and subsequent production and roll-out for public use.
5. Phase IV post-marketing surveillance
- To monitor adverse events
- To study long-term effects of the vaccine
Outcome: This enables determination of effectiveness of the vaccine in routine use setting. Since this phase involves vaccine administration in larger numbers of individuals with varied clinical/health features than in the previous phases, the actual assessment of the vaccine-enabled protection is possible.
How is the vaccine development and approval process different in pandemic times?
Traditional vaccine development consists of a discovery phase, which includes an exploratory phase and pre-clinical stages. In the exploratory phase, vaccines are designed (time taken is usually in years), followed by preclinical experiments which include exploratory as well as formal preclinical experiments and toxicology studies as mentioned here. Please see the previous question for a description of phase trials in normal (non-pandemic) times.
In the case of SARS-CoV‑2 vaccine development during the COVID-19 pandemic, the discovery phase has taken months (instead of years) because of knowledge gained from vaccine development for SARS-CoV and MERS-CoV. During the clinical development phase, there has been overlap of phase 1, 2 and 3 clinical trials, and the overall clinical trials time has been in months, followed by large scale vaccine production. This is followed by vaccine license application and approval (1−2 months). The vaccine is approved in a pandemic only if it is safe, efficacious and the benefits outweigh the risks, as mentioned here. Thus the traditional time of vaccine development during the pandemic is reduced from 15 years to 10 – 18 months.
What does emergency use authorization (EUA) mean and how is EUA different from “approval” for vaccine candidates?
In the USA, during an emergency, like a pandemic, it may not be possible to have all the evidence that the Food and Drug Administration (FDA) would usually have before approving a vaccine. When there is a declared emergency, such as during a pandemic, the FDA can make a judgment that it is worth releasing a vaccine for broader use even without all the evidence that would fully establish its effectiveness and safety. If there is evidence that strongly suggests that patients have benefitted from a treatment or test, the agency can issue an EUA to make it available. EUA is different from “approval” in that it authorizes FDA to facilitate the availability of an unapproved product, or unapproved use of an approved product, during a declared state of emergency.
What does “restricted use” mean, since approval for COVID vaccines in India has been granted as “restricted use in emergency situation”?
This concern has also been raised in a recent Lancet report. There is no definition provided by the Government, but in a press conference, Drugs Controller General of India (DCGI) explained that “India’s first indigenous vaccine against COVID-19 has been approved for restricted use. This means it should not be given to everyone. Only those in extreme need of it based on his/her medical condition will be given the vaccine.” Later on, it was noted that children, pregnant women, the elderly, or persons with co-morbidities should not be given the vaccine.
In the Indian regulatory system, is there a provision for EUA?
According to news reports published in Hindustan times, Times of India, and DGCI Press release on EUA for the Serum institute and Bharat Biotech vaccines, along with approval for Cadila Healthcare Vaccine Phase 3 trials, there is no mention of the phrase ‘Emergency Use Approval’ or EUA in the Indian regulatory system. However, in the New Drugs and Clinical Trials Rules 2019, in the Second Schedule under 2) A) a), there is a provision for granting accelerated approval in special situations (“Accelerated approval process may be allowed to a new drug for a disease or condition, taking into account its severity, rarity, or prevalence and the availability or lack of alternative treatments, provided that there is a prima facie case of the product being of meaningful therapeutic benefit over the existing treatment”).
What is “efficacy” for a vaccine, and why do we need phase 3 trials to estimate it?
The efficacy of a vaccine is the percentage reduction in disease incidence in a vaccinated group, as compared to a control group under optimal conditions such as a randomized controlled clinical trial. As outlined in answer to the second question above, the objective of trials at phase 1 and 2 is to determine side effects, safety, dosage, and immunogenicity. It is only during the phase 3 trial that it can be calculated how effective a vaccine candidate is, as there is a placebo/control arm that consists of volunteers to whom the test vaccine is not given, and a test arm consisting of volunteers to whom the vaccine is given. The disease incidence can be calculated in both groups and compared to calculate the efficacy of the vaccine.
Such a trial is also needed to determine efficacy in different target populations. If the efficacy of a vaccine is even 50%, it means 50% fewer or half as many vaccinated individuals got severe disease as compared to people given placebo or in the control arm. So even if the efficacy of a vaccine is lower than 90%, as reported for some of the most efficacious COVID19 vaccines (Moderna and Pfizer), there is still significant benefit to the population from individuals getting vaccinated.
Before being authorised for general use, or even for emergency authorisation, a vaccine candidate must first pass phase 3 clinical trials (see note on approval process above). The vaccine candidate needs to be administered to tens of thousands of volunteers, to make absolutely sure it is safe. Also, these volunteers then need to be tracked for some months, to make sure they are protected from getting infected in real-world conditions. Around the world, and also in India, vaccine candidates have been authorised for emergency use after clearing phase 3 clinical trials. Such clearance is typically accompanied by the publication and release of phase 3 trial data. Concerns have even been raised over emergency use approval for COVID vaccines. Bharat Biotech’s Covaxin candidate has been authorised for emergency use while simultaneously being in Phase 3 clinical trials. This is inconsistent with the established policy on vaccine candidate approval (Hindu article, see note on approval above).
How is vaccine safety estimated and how safe are the COVID19 vaccines?
Covishield and Covaxin both have no safety concerns as they have done well in phase 1 trials. Immunogenicity is also clear from phase 2 trials. ChAdOx1 nCov-19 (the vaccine from Oxford University — AstraZeneca which is manufactured as Covishield by Serum Institute India) was subjected to randomised phase1 clinical trials in the UK. 1077 participants took part of which 537 were given the Covid vaccine. Here a small set of 56 participants who got the vaccine also received paracetamol as part of the study. Fatigue and headache were the most commonly reported symptoms. Other adverse reaction included muscle ache, malaise, chills and feeling feverish. The severity and intensity of local and systemic reactions were highest on day 1 after vaccination. ChAdOx1 nCoV-19 was safe, tolerated, and immunogenic, while reactogenicity was reduced with paracetamol.
Covaxin underwent randomised phase 1 clinical trials involving 375 participants of whom 300 were given the vaccine and 75 the placebo. It was found that the most common adverse event was pain at the injection site, followed by headache, fatigue, and fever. The overall incidence of solicited local and systemic adverse events in the study was 14 – 21% in the vaccine treated cases.
What are some reported side effects of the vaccines?
Common side effects include redness, tenderness, pain at the site of injection, the feeling of being sick/unwell, fatigue, headache, chills or feeling feverish, nausea, muscle pain/body pain/joint pain, other flu-like symptoms, including runny nose. Uncommon side effects are dizziness, decreased appetite, abdominal pain, excessive sweating, itchy skin. Any untoward medical event after vaccination is considered an Adverse Event (AE) and must be reported to the concerned officials. If the AE is related to the vaccine it is called an Adverse Drug Reaction (ADR).
A cross-sectional online survey was done involving 5396 people that included questions pertaining to the immediate post-vaccination experience in India. As was reported “Tiredness, myalgia and fever were most commonly reported. These symptoms were consistent with an immune response commonly associated with vaccines and correlated with the findings from previously published phase 2⁄3 trials. In 90% of cases, the symptoms were either milder than expected or meeting the expectation of the vaccine recipient. No serious events were reported. Symptoms were more common among younger individuals. There was no difference in symptoms among those who had a past history of COVID-19.”
How effective are the current vaccines against new COVID-19 virus variants?
Over time, viruses naturally accumulate changes in their genetic sequence. The more they multiply in number, the higher the chances of mutations. While most changes (mutations) are of little to no consequence, sometimes the virus acquires a mutation that gives it an advantage over its original form (variant), making it more transmissible or more infectious. The chances of new virus variants emerging are higher if more people are infected, as it is multiplying more.
The SARS-CoV‑2 virus uses its Spike protein to enter the host body by binding to a specific protein on human cells called the ACE2 receptor. Thus, mutations in the gene for the Spike protein can potentially facilitate better affinity or binding and enable easier entry into the host cell, as was the case with the D614G mutation (which has been the globally prevalent SARS-CoV‑2 variant in circulation for the majority of the year 2020). Mutations that enhance viral fitness need to be identified and monitored to check if the available Covid-19 vaccines are effective in raising an immune response in the human host.
The currently approved vaccines raise a host immune response against multiple parts of the virus. So, even if one of the parts of the virus changes due to a new mutation, the vaccine will identify the other parts. This decreases the chances of newer variants escaping the vaccine. Even as the vaccination process has now been initiated globally, the current vaccines need to be evaluated for their potential against the new viral mutations as they arise.
Variants that are of the greatest concern currently include those that have changes (mutations) in the Spike protein that causes immune escape or the Spike mutations N501Y (located in the viral receptor binding site for cell entry and increases binding to the human receptor) and/or E484K (reduced susceptibility to neutralization by antibodies), shared by variants that were first identified in the United Kingdom, South Africa and Brazil (called 501Y.V1, 501Y.V2 and 501Y.V3 respectively).
A key factor with the new mRNA based vaccines (Pfizer’s and Moderna’s) is that they appear to produce a heightened immune response, such that a drop in the level of neutralization antibody detected with these variants may not be highly worrisome, and they may still provide effective immunity. Pfizer’s vaccine shows a reduction in neutralization against engineered mutations found in variants of concern; however, the degree of reduction is variable in serum from different individuals and is not very huge. Moderna has also demonstrated reduced but still significant neutralization against the variants following mRNA-1273 vaccination. They are however looking to develop booster shots and/or altered vaccines for emerging variants; the mRNA vaccines may probably be the fastest to tweak and redesign (possibly within a few weeks).
The vaccines by Johnson & Johnson and Novavax may also be less effective against some of the new variants, especially the variant identified in South Africa, although new data are being released at a rapid pace. Novavax released data from clinical trials showing that its experimental vaccine, designed to combat the original virus, was about 89% effective against the current COVID-19 virus strain, 85% effective against the variant identified in the United Kingdom, but less than 50% effective against the one identified in South Africa. Bharat Biotech has also released information showing that their vaccine works against the variant seen in the UK — still in a clinical trial mode, though approved in India, the vaccine was found to be fully effective against the N501Y mutation.
The Serum Institute of India, currently offering the Oxford-AstraZeneca vaccine that may have lower efficacy with emerging variants, is planning to conduct trials to bring a second vaccine called Covovax (which is based on Novavax) that may be more effective against them. Adenovirus vector-based vaccines are also relatively easy to update, though they may take longer than the mRNA based ones.
Evidence shows that most of the vaccines will confer some degree of protection from the currently evolved variants, though the combination of mutations carried in a particular variant, its prevalence in a region, and the host immune response will ultimately decide the final efficacy of any vaccine.
The original explainer by ISRC lists some of the tests conducted by the various companies for vaccine efficacy against the new variants (Section 2, Q4)
Is it worth taking the vaccines now if new variants are emerging?
The best way to prevent further mutations from arising and accumulating is to avoid giving the virus a chance to replicate, i.e. reducing the number of infected people. This can be safely achieved by vaccinations and hence, the rise of worrying mutations should not be a deterrent for vaccination programs. A possible lowered efficacy to new variants will still provide some degree of protection against the disease and also help stop viral transmission in the population. A recent pre-print has shown that the N501Y mutation in the variant seen in the UK can be neutralised by both convalescent sera (serum from an individual who has overcome a recent COVID-19infection) as well as post-vaccination serum (serum from a vaccinated individual who has mounted an immune response to the COVID-19 vaccine).
Of greater concern is the so-called South African variant that escapes convalescent serum antibodies. It also reduces neutralizing abilities (~6 fold) of mRNA vaccine evoked serum antibodies, but significant neutralization activity still remains. South Africa has paused the roll-out of the AstraZeneca vaccine, following concerns regarding poor efficacy against the variant identified there. Recent work, however, highlights the importance of mRNA vaccines even against such emerging variants.
The WHO has released a statement on 8 February 2021 regarding vaccine efficacy concerns in the light of immune escape variants, affirming that “we need to adjust to the SARS-CoV‑2 viral evolution, including potentially providing future booster shots and adapted vaccines, if found to be scientifically necessary”. However, the statement also highlights the need to prioritize the vaccination of high-risk groups everywhere in order to ensure maximum global protection against new strains and minimize the risk of transmission.
Does being vaccinated prevent people from infecting others?
The COVID-19 virus infects the wet, soft, mucosal tissues first, as it enters the body through the nose, mouth or eyes. At first, the virus replicates in the upper passages of the nose and throat, not causing severe disease for a few days. The infected person releases these replicated viruses into the air around them, by coughing, speaking or even just breathing, potentially infecting others around them. Only over a period of days, in a second phase, does the virus then spread into the lungs, where severe disease might be caused. So viral replication and spread happens early on and in a different part of the body from severe disease.
Many of the vaccines that have been authorised around the world have released phase 3 clinical trial data, but these have only been tested for efficacy at preventing severe disease (see also study results for Moderna , Pfizer, AstraZeneca vaccines) ie. we know they prevent the second phase of the infection, in the lungs. But they could still cause the first phase of infection, in the upper respiratory mucosa. In fact, we know that vaccines injected into the arm make the body produce a type of antibodies (IgGs) that circulate in the blood, and are effective at protecting the lungs. But they do not reach mucous tissue. For protection there, we would need another class of antibodies (IgA), which are elicited by different, nasal vaccines.
We know that when a person gets infected with COVID19, their body’s first defensive response is IgA production in mucosal tissues, followed later on by IgG in the blood. In fact, among people vaccinated with the Oxford — AstraZeneca vaccine (Covishield in India), a study found 67% fewer people had virus in their nasal swabs as opposed to unvaccinated people. But even among the vaccinated, people still produced the virus and could potentially spread the infection.
The good news is that the new COVID19 vaccine injections we will get in our arms will give us protection from severe disease in our lungs, potentially for years. But we might still get mild or symptom-free infections in the mucous tissue in our noses and throats and spread the virus to others. So even after getting vaccinated, we need to continue to wear masks and physically distance until population infection numbers come down.
This is a companion discussion topic for the original entry at https://indiabioscience.org/columns/indian-scenario/covid-19-vaccines-in-india-frequently-asked-questions